This application claims the benefit of foreign priority under 35 U.S.C. xc2xa7119 of German patent application no. 10060807.8-44, filed on Dec. 7, 2000 the contents of which are incorporated by reference herein.
The present invention relates to ortho, ortho-substituted nitrogen-containing bisaryl compounds. Embodiments of the invention include processes for their preparation, their use as medicaments, and pharmaceutical preparations comprising them.
The present invention relates to ortho, ortho-substituted nitrogen-containing bisaryl compounds of the formula I, 
in which:
A1, A2, A3, A4, A5, A6, A7 and A8
independently of one another are chosen from nitrogen, CH and CR(5), at least one of these groups being nitrogen and at least 4 of these groups being CH;
R(1), is C(O)OR(9), SO2R(10), COR(11), C(O)NR(12)R(13) or C(S)NR(12)R(13);
wherein R(9), R(10), R(11) and R(12)
independently of one another are CxH2xxe2x80x94R(14);
where x is 0, 1, 2, 3 or 4, and
x cannot be 0 if R(14) is OR(15) or SO2Me;
R(14) is alkyl having 1, 2, 3, 4, 5 or 8 atoms, cycloalkyl having 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms, CF3, C2F5, C3F7, CH2F, CHF2, OR(15), SO2Me, substituted or unsubstituted phenyl,
substituted or unsubstituted naphthyl, substituted or unsubstituted biphenylyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl or a substituted or unsubstituted N-containing heteroaromatic having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,
where the substituted phenyl, substituted naphthyl, substituted biphenylyl, substituted furyl, substituted thienyl and the substituted N-containing heteroaromatic are each independently substituted by 1, 2 or 3 substituents chosen from F, Cl, Br, I, CH3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, CH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(15) is alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF3 substituted phenyl or unsubstituted phenyl,
wherein the substituted phenyl is substituted by 1, 2 or 3 substituents chosen from F, Cl, Br, I, CH3, NO2, CN, COOMe, CONH2, COMe, NH2, CH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; and
R(13) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CH3;
R(2) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CH3;
R(3) is CyH2yxe2x80x94R(16);
where y is 0, 1, 2, 3or 4, and
y cannot be 0 if R(16) is OR(17) or SO2Me;
R(16) is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms, CF3, C2F5, OCF7, CH2F, CHF2, OR(17), SO2Me, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl or a substituted or unsubstituted N-containing heteroaromatic having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,
where the substituted phenyl, substituted naphthyl, substituted furyl, substituted thienyl and the substituted N-containing heteroaromatic are each independently substituted by 1, 2 or 3 substituents chosen from F, Cl, Br, I, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; and
R(17) is hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF3, substituted phenyl, unsubstituted phenyl, substituted 2-, 3- or 4-pyridyl, or unsubstituted 2-, 3- or 4-pyridyl,
where the substituted phenyl and substituted 2-, 3- or 4-pyridyl are each independently substituted by 1, 2 or 3 substituents chosen from F, Cl, Br, I, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, CH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
or
R(3) is CHR(18)R(19);
where R(18) is hydrogen or CzH2zxe2x80x94R(16), where R(16) is defined as indicated above;
z is 0, 1, 2 or 3;
R(19) is COCH, CONH2, CONR(20)R(21), COOR(22) or CH2OH;
R(20) is hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms, CvH2vxe2x80x94CF3, substituted CwH2w-phenyl or unsubstituted CwH2w-phenyl,
where the phenyl ring of the substituted CwH2w-phenyl is substituted by 1, 2 or 3 substituents chosen from F, Cl, Br, I, CF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
v is 0, 1, 2 or 3;
w is 0, 1, 2 or 3;
R(21) is hydrogen or alkyl having 1, 2, 3, 4 or 5 carbon atoms; and
R(22) is alkyl having 1, 2, 3, 4 or 5 carbon atoms;
R(4) is hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF3;
or
R(3) and R(4)
together are a chain of 4 or 5 methylene groups, of which one methylene group can be replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94N(methyl)- or xe2x80x94N(benzyl)-;
R(5) is independently of one another chosen from F, Cl, Br, I, CF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino, where in the case that more than one of the radicals A1 to A8 have the meaning CR(5), the radicals R(5) are defined independently of one another.
R(30) and R(31)
independently of one another are hydrogen or alkyl having 1, 2 or 3 carbon atoms;
or
R(30) and R(31)
together are oxygen or a chain of 2 methylene groups
and their pharmaceutically acceptable salts.
In one embodiment, the compounds of formula 1 are those in which:
A1, A2, A3, A4, A5, A6, A7 and A8
independently of one another are chosen from nitrogen, CH and CR(5), at least one of these groups being nitrogen and at least 4 of these groups being CH;
R(1) is C(O)OR(9), SO2R(10), COR(11) or C(O)NR(12)R(13) R(9), R(10), R(11) and R(12)
independently of one another are CxH2xxe2x80x94R(14);
where x is 0, 1, 2, 3 or 4; and
x cannot be 0 if R(14) is OR(15);
R(14) is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF3, OR(15), substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted biphenylyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl or a substituted or unsubstituted N-containing heteroaromatic having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,
where substituted phenyl, substituted naphthyl, substituted biphenylyl, substituted furyl, substituted thienyl and the substituted N-containing heteroaromatic are each independently substituted by 1, 2 or 3 substituents chosen from F, Cl, Br, I, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(15) is alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF3, substituted phenyl or unsubstituted phenyl,
wherein the substituted phenyl is substituted by 1, 2 or 3 substituents chosen from F, Cl, Br, I, CF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(13) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CF3;
R(2) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CF3;
R(3) is CyH2yxe2x80x94R(16);
where y is 0, 1, 2, 3 or 4, and
y cannot be 0 it R(16) is OR(17) or SO2Me;
R(16) is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8, 9, carbon atoms, CF3, OR(17), SO2Me, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl or a substituted or unsubstituted N-containing heteroaromatic having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,
where the substituted phenyl, substituted naphthyl, substituted furyl, substituted thienyl and the substituted N-containing heteroaromatic are each independently substituted by 1, 2 or 3 substituents chosen from F, Cl, Br, I, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(17) is hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF3, substituted phenyl, unsubstituted phenyl, substituted 2-, 3- or 4-pyridyl, or unsubstituted 2-, 3- or 4-pyridyl
where the substituted phenyl or substituted 2-, 3- or 4-pyridyl are each independently substituted by 1, 2 or 3 substituents chosen from F, Cl, Br, I, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
or
R(3) is CHR(18)R(19);
where R(18)is hydrogen or CzH2zxe2x80x94R(16), where R(16)is defined as indicated above;
z is 0, 1, 2 or 3;
R(19) is CONH2, CONR(20)R(21), COOR(22) or CH2OH;
R(20) is hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms, CzH2vxe2x80x94CF3, substituted CwH2w-phenyl, or substituted CwH2w-phenyl,
where the phenyl ring of the substituted CwH2w-phenyl is substituted by 1, 2 or 3 substituents chosen from F, Cl, Br, I, CF3, OCF3, NO2, ON, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
v is 0, 1, 2 or 3;
w is 0, 1, 2 or 3;
R(21) is hydrogen or alkyl having 1, 2, 3, 4 or 5 carbon atoms; and
R(22) is alkyl having 1, 2, 3, 4 or 5 carbon atoms;
R(4) is hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF3;
R(5) is independently of one another chosen from F, Cl, Br, I, CF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(30) and R(31)
independently of one another are hydrogen or alkyl having 1, 2 or 3 carbon atoms;
or
R(30) and R(31)
are a chain of 2 methylene groups
and their pharmaceutically acceptable salts.
In another embodiment, the compounds of the formula I are those in which: A1, A2, A3, A4, A5, A6, A7 and A8 independently of one another are chosen from nitrogen, CH and CR(5), where at least one and at most two of these groups are nitrogen and at least 4 of these groups are CH.
For example, in one embodiment, compounds of the formula I are those in which:
A1, A2, A3, A4, A5, A6, A7 and A8
independently of one another are chosen from nitrogen, CH and CR(5), where at least one and at most two of these groups are nitrogen and at least 4 of these groups are CH;
R(1) is C(O)OR(9), SO2R(10), COR(11) or C(O)NR(12)R(13); R(9), R(10), R(11) and R(12)
independently of one another are CxH2xxe2x80x94R(14);
where x is 0, 1, 2, 3 or 4,
x cannot be 0 if R(14) is OR(15);
R(14) is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF3, OR(15), substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted biphenylyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl or a substituted or unsubstituted N-containing heteroaromatic having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms;
where the substituted phenyl, substituted naphthyl, substituted biphenylyl, substituted furyl, substituted thienyl and the substituted N-containing heteroaromatic are each independently substituted by 1, 2 or 3 substituents chosen from F, Cl, Br, I, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(15) is alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF3 substituted phenyl or unsubstituted phenyl,
wherein the substituted phenyl is substituted by 1, 2 or 3 substituents chosen from F, Cl, Br, I, CF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(13) is hydrogen
R(2) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;
R(3) is CHR(18)R(19);
R(18) is hydrogen or CzH2zxe2x80x94R(16),
where R(16)is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8, 9, carbon atoms, CF3, OR(17), SO2Me, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl or a substituted or unsubstituted N-containing heteroaromatic having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,
where the substituted phenyl, substituted naphthyl, substituted furyl, substituted thienyl and the substituted N-containing heteroaromatic are each independently substituted by 1, 2 or 3 substituents chosen from F, Cl, Br, I, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
z is 0, 1, 2 or 3;
R(19) is CONH2, CONR(20)R(21), COOR(22) or CH2OH;
R(20) is hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms, CvH2vxe2x80x94CF3, substituted CwH2w-phenyl, or unsubstituted CwH2w-phenyl
where the phenyl ring of the substituted CwH2w-phenyl is substituted by 1, 2 or 3 substituents chosen from F, Cl, Br, I, CF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
v is 0, 1, 2 or 3;
w is 0, 1, 2 or 3;
R(21) is hydrogen or alkyl having 1, 2, 3, 4 or 5 carbon atoms;
R(22) is alkyl having 1, 2, 3, 4 or 5 carbon atoms;
R(4) is hydrogen or alkyl having 1 or 2 carbon atoms;
R(5) is independently of one another chosen from F, Cl, Br, I, CF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino;
R(30) and R(31)
independently of one another are hydrogen or methyl;
and their pharmaceutically acceptable salts.
In a further embodiment, compounds of the formula I are those in which:
A1, A2, A3, A4, A5, A6, A7 and A8
independently of one another are chosen from nitrogen, CH and OR(5), where at least one and at most two of these groups are nitrogen and at least 4 of these groups are CH;
R(1) is C(O)OR(9), SO2R(10), COR(11) or C(O)NR(12)R(13);
where R(9), R(10), R(11) and R(12)
independently of one another are CxH2xxe2x80x94R(14);
x is 0, 1, 2, 3 or 4;
R(14) is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF3, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted biphenylyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl or a substituted or unsubstituted N-containing heteroaromatic having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,
where the substituted phenyl, substituted naphthyl, substituted biphenylyl, substituted furyl, substituted thienyl and the substituted N-containing heteroaromatic are each independently substituted by 1, 2 or 3 substituents chosen from F, Cl, Br, I, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(13) is hydrogen;
R(2) is hydrogen or methyl;
R(3) is CyH2yxe2x80x94R(16);
where y is 0, 1, 2, 3 or 4; and
y cannot be 0 if R(16) is OR(17);
R(16) is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8, 9, carbon atoms, CF3, OR(17), SO2Me, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl or a substituted or unsubstituted N-containing heteroaromatic having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,
where the substituted phenyl, substituted naphthyl, substituted furyl, substituted thienyl and the substituted N-containing heteroaromatic are each independently substituted by 1, 2 or 3 substituents chosen from F, Cl, Br, I, CF3, NO2, OCF3, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(17) is hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF3, substituted phenyl, unsubstituted phenyl, substituted 2-, 3- or 4-pyridyl, or unsubstituted 2-, 3- or 4-pyridyl
where the substituted phenyl or substituted 2-, 3- or 4-pyridyl are each independently substituted by 1, 2 or 3 substituents chosen from F, Cl, Br, I, CF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(4) is hydrogen or alkyl having 1 or 2 carbon atoms;
R(5) is independently of one another chosen from F, Cl, Br, I, CF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino;
R(30) and R(31)
independently of one another are hydrogen or methyl;
and their pharmaceutically acceptable salts.
In another embodiment, the compounds of the formula I are those in which A4 is nitrogen and A1, A2, A3, A5, A6, A7 and A8 independently of one another are chosen from CH and CR(5), where at least 5 of these groups are CH; and their pharmaceutically acceptable salts.
In an even further embodiment, the compounds of the formula I are those in which:
R(1) is C(O)OR(9), SO2R(10), COR(11) or C(O)NR(12)R(13);
where R(9), R(10), R(11) and R(12) independently of one another are CxH2xxe2x80x94R(14);
where x is 0, 1, 2 or 3;
R(14) is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF3, substituted phenyl, unsubstituted phenyl, substituted pyridyl, or unsubstituted pyridyl
where the substituted phenyl and substituted pyridyl are each independently substituted by 1 or 2 substituents chosen from F, Cl, Br, I, CF3, OCF3, OH, alkyl having 1, 2 or 3 carbon atoms or alkoxy having 1 or 2 carbon atoms;
R(13) is hydrogen;
R(2) is hydrogen;
R(3) is CyH2yxe2x80x94R(16);
y is 0, 1 or 2;
R(16) is alkyl having 1, 2, 3 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF3, substituted phenyl, unsubstituted phenyl, substituted pyridyl, or unsubstituted pyridyl where the substituted phenyl and substituted pyridyl are each independently substituted by 1 or 2 substituents chosen from F, Cl, CF3, alkyl having 1, 2 or 3 carbon atoms and alkoxy having 1 or 2 carbon atoms;
R(4) is hydrogen;
R(5) is independently of one another chosen from F, Cl, CF3, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2 or 3 carbon atoms and alkoxy having 1 or 2 carbon atoms;
R(30) and R(31)
independently of one another are hydrogen or methyl; and their pharmaceutically acceptable salts.
Another example of the compounds of the formula I are those in which:
R(1) is C(O)OR(9) or COR(11);
R(9) and R(11)
independently of one another are CxH2xxe2x80x94R(14);
where x is 0, 1, 2 or 3;
R(14) is cycloalkyl having 5 or 6 carbon atoms substituted phenyl, or unsubstituted phenyl
where the substituted phenyl is substituted by 1 or 2 substituents chosen from F, Cl, Br, I, CF3, OCF3, OH, alkyl having 1, 2 or 3 carbon atoms or alkoxy having 1 or 2 carbon atoms;
R(2) is hydrogen;
R(3) is CyH2yxe2x80x94R(16);
y is 0, 1, or 2;
R(16) is alkyl having 1, 2 or 3 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, substituted phenyl, unsubstituted phenyl, substituted pyridyl, or unsubstituted pyridyl,
where the substituted phenyl and substituted pyridyl are each independently substituted by 1 or 2 substituents chosen from F, Cl, CF3, OCF3, alkyl having 1, 2 or 3 carbon atoms and alkoxy having 1 or 2 carbon atoms;
R(4) is hydrogen;
R(5) is independently of one another chosen from F, Cl, alkyl having 1, 2, 3 carbon atoms and alkoxy having 1 or 2 carbon atoms;
R(30) and R(31)
are hydrogen;
and their pharmaceutically acceptable salts.
The invention also relates to the preparation of the compounds of the invention and to their use, in particular in pharmaceuticals.
The compounds according to the invention were hitherto, to the best of our knowledge, unknown. Not to be limited as to theory, they act on the xe2x80x98Kv1.5 potassium channelxe2x80x99 and, as an ultra-rapidly activating delayed rectifier, inhibit a designated potassium current in the human atrium. The compounds may therefore be particularly suitable as novel antiarrhythmic active compounds, in particular for the treatment and prophylaxis of atrial arrhythmias, e.g. (atrial fibrillation AF) or atrial flutters.
Atrial fibrillation (AF) and atrial flutters are the most frequent persistent cardiac arrhythmias. Occurrence increases with increasing age and frequently leads to fatal sequelae, such as cerebral stroke. AF affects about 1 million Americans annually and leads to more than 80,000 cases of stroke each year in the USA. The presently customary antiarrhythmics of classes I and III reduce the reoccurrence rate of AF, but are only of restricted use because of their potential proarrhythmic side effects. There is therefore a great medical need for the development of better medicaments for treating atrial arrhythmias (S. Nattel, Am. Heart J. 130, 1995, 1094-1106; xe2x80x9cNewer developments in the management of atrial fibrillationxe2x80x9d).
It has been shown that most supraventricular arrhythmias are subject to xe2x80x9creentryxe2x80x9d excavatory waves. Such reentries occur when the cardiac tissue has a slow conductivity and, at the same time, very short refractory periods. Increasing the myocardial refractory period by prolonging the action potential is a recognized mechanism of ending arrhythmias or preventing their formation (T. J. Colatsky et al, Drug Dev. Res. 19, 1990, 129-140; xe2x80x9cPotassium channels as targets for antiarrhythmic drug actionxe2x80x9d). The length of the action potential is essentially determined by the extent of repolarizing K+ currents which flow out of the cell from various K+ channels. The primary focus is ascribed here to the xe2x80x98delayed rectifierxe2x80x99 IK, which consists of 3 different components, IKr, IKs and IKur.
Most known class III antiarrhythmics (e.g. dofetilide, E4031 and d-sotalol) mainly or exclusively block the rapidly activating potassium channel IKr, which can be demonstrated both in cells of the human ventricle and in the atrium. However, it has been shown that these compounds have an increased proarrhythmic risk at low or normal heart rates, arrhythmias which are designated as xe2x80x9ctorsades de pointesxe2x80x9d being observed (D. M. Roden, Am. J. Cardiol. 72, 1993, 44B-49B; xe2x80x9cCurrent status of class III antiarrhythmic drug therapyxe2x80x9d). In addition to this high, in some cases fatal risk at a low rate, a decrease in the activity has been found for the IKr blockers under the conditions of tachycardia, in which the action is especially needed (xe2x80x9cnegative use-dependencexe2x80x9d).
While some of these disadvantages can possibly be overcome by blockers of the slow-activating component (IKs), their activity has hitherto been unconfirmed, since no clinical investigations using IKs channel blockers are known.
The xe2x80x9cparticularly rapidlyxe2x80x9d activating and very slowly inactivating component of the delayed rectifier IKur (=ultra-rapidly activating delayed rectifier), which corresponds to the Kv.1.5 channel, plays a particularly large role in the repolarization period in the human atrium. Inhibition of the IKur potassium outward current is thus, in comparison with the inhibition of IKr or IKs, a particularly effective method for prolonging the atrial action potential and thus for the ending or prevention of atrial arrhythmias. Mathematical models of the human action potential suggest that the positive effect of a blockade of the IKur, especially under the pathological conditions of chronic atrial fibrillation, should be particularly pronounced (M. Courtemanche, R. J. Ramirez, S. Nattel, Cardiovascular Research 1999, 42, 477-489: xe2x80x9cIonic targets for drug therapy and atrial fibrillation-induced electrical remodeling: insights from a mathematical modelxe2x80x9d).
In contrast to IKr and IKs, which also occur in the human ventricle, the IKur indeed plays an important role in the human atrium, but not in the ventricle. For this reason, in the case of inhibition of the IKur flow, in contrast to the blockade of IKr IKs, the risk of a proarrhythmic action on the ventricle is excluded from the start (Z. Wang et al, Circ. Res. 73, 1993,1061-1076: xe2x80x9cSustained Depolarisation-Induced Outward Current in Human Atrial Myocytesxe2x80x9d; G.-R. Li et al, Circ. Res. 78,1996, 689-696: xe2x80x9cEvidence for Two Components of Delayed Rectifier K+-Current in Human Ventricular Myocytesxe2x80x9d; G. J. Amos et al, J. Physiol. 491, 1996, 31-50: xe2x80x9cdifferences between outward currents of human atrial and subepicardial ventricular myocytesxe2x80x9d).
Antiarrhythmics which act via selective blockade of the IKur current or Kv1.5 channel have hitherto not been available, however, on the market. For numerous pharmaceutical active compounds (e.g. tedisamil, bupivacaine or sertindole), a blocking action on the Kv1.5 channel has indeed been described, but the Kv1.5 blockade here is in each case only a side effect in addition to other main actions of the substances.
WO 98 04 521 and WO 9937607 claim aminoindans and aminotetrahydro-naphthalenes as potassium channel blockers which block the Kv1.5 channel. Likewise, structurally related aminochromans are claimed as Kv1.5 blockers in WO 0012077. The application WO 9992891 claims thiazolidinones which likewise block the potassium channel. The applications WO 98 18 475 and WO 98 18 476 claim the use of various pyridazinones and phosphine oxides as antiarrhythmics which should act via blockade of the Ikur. The same compounds were originally also described, however, as immunosuppressants (WO 96 25 936). The compounds described in these mentioned applications are structurally completely different to the compounds according to the invention of this application. For all compounds claimed in the abovementioned applications, no clinical data are known to use.
It has now surprisingly been found that the ortho, ortho-substituted nitrogen-containing bisaryl compounds described here are potent blockers of the human Kv1.5 channel. They may therefore, for example, be used as novel antiarrhythmics having a particularly advantageous safety profile. For example, the compounds may be suitable for the treatment of supraventricular arrhythmias, e.g. atrial fibrillation or atrial flutters. The compounds may also, for example, be employed for the termination of existing atrial fibrillation or flutters for the recovery of the sinus rhythm (cardio version). Moreover, the substances may reduce the susceptibility to the formation of new fibrillation events (maintenance of the sinus rhythm, prophylaxis).
The compounds according to the invention were hitherto, to the best of our knowledge, unknown.
According to the invention, alkyl radicals and alkylene radicals can be straight-chain or branched. This also applies to the alkylene radicals of the formulae CxH2x, CyH2y, CzH2z, CvH2v and CwH2w. Alkyl radicals and alkylene radicals can also be straight-chain or branched if they are substituted or are contained in other radicals, e.g. in an alkoxy radical or in a fluorinated alkyl radical. Examples of alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3,3-dimethylbutyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl. The divalent radicals derived from these radicals, e.g. methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 2,2-propylene, 1,3-propylene, 1,1-butylene, 1,4-butylene, 1,5-pentylene, 2,2-dimethyl-1,3-propylene, 1,6-hexylene, etc. are examples of alkylene radicals.
Cycloalkyl radicals can likewise be branched. Examples of cycloalkyl radicals having 3 to 11 carbon atoms are cyclopropyl, cyclobutyl, 1-methylcyclopropyl, 2-methylcyclopropyl, cyclopentyl, 2-methylcyclobutyl, 3-methylcyclobutyl, cyclopentyl, cyclohexyl, 2-methylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, menthyl, cycloheptyl, cyclooctyl etc.
N-containing heteroaromatics having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms are in particular 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 1,2,3-triazol-1-, -4- or 5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-oxadiazol-2-yl or -5-yl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-indazyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl. Also included are the corresponding N-oxides of these compounds, i.e., for example, 1-oxy-2-, -3- or -4-pyridyl.
In one embodiment, N-containing heterocycles are pyrrolyl, imidazolyl, quinolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl.
Pyridyl is either 2-, 3- or 4-pyridyl. Thienyl is either 2- or 3-thienyl. Furyl is either 2- or 3-furyl.
Monosubstituted phenyl radicals can be substituted in the 2-, the 3- or the 4-position, disubstituted in the 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-position, or trisubstituted in the 2,3,4-, 2,3,5-, 2,3,6-, 2,4,5-, 2,4,6- or 3,4,5-position. Correspondingly, the same analogously also applies to the N-containing heteroaromatics, the thiophene or the furyl radical.
In the case of di- or trisubstitution of a radical, the substituents can be identical or different.
In one embodiment, if R(3) and R(4) together are a chain of 4 or 5 methylene groups of which one methylene group can be replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94 etc., then these radicals together with the nitrogen atom may form a 5- or 6-membered nitrogen heterocycle, such as pyrrolidine, piperidine, morpholine, thiomorpholine etc.
In a further embodiment, if the compounds of the formula I contain one or more acidic or basic groups or one or more basic heterocycles, the invention may also include the corresponding physiologically or toxicologically tolerable salts, in particular the pharmaceutically utilizable salts. Thus the compounds of the formula I which carry acidic groups, e.g. one or more COOH groups, can be used, for example, as alkali metal salts, preferably sodium or potassium salts, or as alkaline earth metal salts, e.g. calcium or magnesium salts, or as ammonium salts, e.g. as salts with ammonia or organic amines or amino acids. Compounds of the formula I which carry one or more basic, i.e. protonatable, groups or contain one or more basic heterocyclic rings can also be used in the form of their physiologically tolerable acid addition salts with inorganic or organic acids, for example as hydrochlorides, phosphates, sulfates, methanesulfonates, acetates, lactates, maleates, fumarates, malates, gluconates, etc. If the compounds of the formula I simultaneously contain acidic and basic groups in the molecule, in addition to the salt forms described, the invention also includes internal salts, xe2x80x98betainesxe2x80x99. Salts may be obtained from the compounds of the formula I according to customary processes, for example, by combination with an acid or base in a solvent or dispersant or alternatively from other salts by anion exchange.
In one embodiment, if appropriately substituted, the compounds of the formula I may be present in stereoisomeric forms. If the compounds of the formula I contain one or more centers of asymmetry, these may independently of one another have the S configuration or the R configuration. The invention includes all possible stereoisomers, e.g. enantiomers or diastereomers, and mixtures of two or more stereoisomeric forms, e.g. enantiomers and/or diastereomers, in any desired ratios. The invention thus includes enantiomers, e.g. in enantiomeric pure form, both as levo- and dextrorotatary antipodes, and in the form of mixtures of the two enantiomers in different ratios or in the form of racemates. Individual stereoisomers can be prepared, if desired, by separation of a mixture according to customary methods or, for example, by stereoselective synthesis. If mobile hydrogen atoms are present, the present invention also includes all tautomeric forms of the compounds of the formula I.
The compounds of the formula I may be prepared by different chemical processes, which are likewise encompassed by the present invention. Some typical routes are outlined in the reaction sequences designated below as Schemes 1 to 4. A1 to A8 and the radicals R(1) to R(4), R(30) and R (31) are in each case defined as indicated above, if not stated otherwise below.
Thus a compound of the formula I, for example, is obtained as in Scheme 1 (method A) or Scheme 2 (method B). 
Bisaryls of the formula IV in which at least one of the ring agoms A1 to A8 is nitrogen may be prepared by palladium-catalyzed Suzuki coupling (which can be carried out, for example, in the presence of Pd[(PPh3)]4 as a catalyst, sodium carbonate as a base and 1,2-dimethoxyethane as a solvent) of an aromatic halide of the formula III with an aromatic boronic acid of the formula III. If R(9) is an easily cleavable radical, such as tert-butyl or benzyl, compounds of the formula V can be obtained, which can then be converted into compounds of the formula I by reaction with reagents R(1)-X and/or R(2)-Y. The reactions of the compounds of the formula V with compounds of the formula R(1)-X correspond, for example, to the known conversion of an amine into a carboxamide, sulfonamide, carbamate, urea or thiourea derivative. The radical X here is a suitable nucleofugic leaving group, such as F, Cl, Br, imidazole, O-succinimide etc.
For the preparation of the compounds of the formula I in which R(1) is C(O)OR(9), i.e. carbamates, compounds of the formula R(1)-X, for example, are used in which X is chlorine or O-succinimide, i.e. chloroformates or succinimidocarbonates.
For the preparation of compounds of the formula I in which R(1)is SO2R(10), i.e. sulfonamides, as a rule compounds of the formula R(1)-X may be used in which X is chlorine, i.e. sulfonyl chlorides.
For the preparation of compounds of the formula I in which R(1) is COR(11), i.e. carboxamides, compounds of the formula R(1)-X, for example, may be used in which X is chlorine, imidazole or acetoxy, i.e. carboxylic acid chlorides, carboxylic acid imidazolides or mixed anhydrides. However, it is also possible, for example, to use the free acids of the formula R(1)-OH in the presence of suitable condensing agents such as carbodiimides or TFFH.
For the preparation of compounds of the formula I in which R(1) is CONR(12)R(13) or C(S)NR(12)R(13), i.e. ureas or thioureas, instead of the compounds of the formula R(1)-X compounds of the formula R(12)N(xe2x95x90Cxe2x95x90O) or R(12)N(xe2x95x90Cxe2x95x90S) may also be used, i.e. isocyanates or isothiocyanates. 
Bisaryls of the formula VIII in which at least one of the ring atoms A is nitrogen may be prepared by palladium-catalyzed Suzuki coupling of an aromatic bromide or iodide of the formula VII with an aromatic boronic acid of the formula II. Hydrolysis of the ester using LiOH affords the free acids of the formula IX which can be converted into the bisaryls of the formula IV by coupling with amines NHR(3)R(4). As described in Scheme 1, cleavage of the labile group R(9) yields compounds of the formula V, which can be further converted into compounds of the formula I.
The abovementioned reactions of the compounds of the formula IX with amines of the formula HNR(3)R(4) correspond to the known conversion of a carboxylic acid to a carboxamide. Numerous methods for carrying out these reactions have been described in the literature. They may be carried out, for example, by activation of the carboxylic acid, e.g. using dicyclohexylcarbodiimide (DCC) or N-ethyl-Nxe2x80x2-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), if appropriate with addition of hydroxybenzotriazole (HOBt) or dimethylaminopyridine (DMAP). However, reactive acid derivatives can also first be synthesized by known methods, e.g. acid chlorides by reaction of the carboxylic acids of the formula IX or using inorganic acid halides, e.g. SOCl2, or acid imidazolides by reaction with carbonyldiimidazole, which are then subsequently reacted with the amines of the formula HNR(3)R(4), if appropriate with addition of an auxiliary base. 
The aromatic boronic acids of the formula II needed in methods A and B can be synthesized from the aromatics or aromatic halides of the formula VI by ortholithiation or halogen-metal exchange followed by reaction with trimethyl borates (or other boric acid triesters) and subsequent acidic hydrolysis. 
The halides of the formula VII employed in method B may be synthesized by procedures known from the literature, for example, and are readily obtainable from the acids of the formula X known from the literature by customary esterification methods. The aromatic ortho-haloamides of the formula III employed in method A are obtainable, for example, according to scheme 4 from the esters of the formula VII, after hydrolysis to the acids X, by coupling with amines NHR(3)R(4). The linkage of the amide bond can be carried out in the ways described above for the reaction of compounds of the formula IX to IV.
In all procedures, it may be appropriate to temporarily protect functional groups in the molecule in certain reaction steps. Such protective group techniques are familiar to the person skilled in the art. The choice of a protective group for possible functional groups and the processes for its introduction and removal are described in the literature and can be adapted to the individual case, if appropriate, without difficulties.
In one embodiment, the compounds of the formula I according to the invention and their physiologically tolerable salts can be used in animals, for example in mammals, including in humans, as pharmaceuticals per se, in mixtures with one another or in the form of pharmaceutical preparations. The present invention, in one embodiment, also relates to the compounds of the formula I and their physiologically tolerable salts for use as pharmaceuticals, their use in the therapy and prophylaxis of the syndromes mentioned and their use for the production of medicaments therefor and of medicaments having K+ channel-blocking action. The present invention furthermore, in a further embodiment, relates to pharmaceutical preparations which, as active constituent, contain an efficacious dose of at least one compound of the formula I and/or of a physiologically tolerable salt thereof in addition to customary, pharmaceutically innocuous vehicles and excipients. The pharmaceutical preparations, for example contain about 0.1 to about 90 percent by weight of the compounds of the formula I and/or their physiologically tolerable salts. The pharmaceutical preparations may, for example, be prepared in a manner known per se. To this end, the compounds of the formula I and/or their physiologically tolerable salts may be brought, together with one or more solid or liquid pharmaceutical vehicles and/or excipients and, if desired, in combination with other pharmaceutically active compounds, into a suitable administration or dose form, which can then be used as a pharmaceutical in human medicine or veterinary medicine.
Pharmaceuticals which contain compounds of the formula I according to the invention and/or their physiologically tolerable salts may, for example, be administered orally, parenterally, e.g. intravenously, rectally, by inhalation or topically, the administration being dependent on the individual case, e.g. the particular clinical picture of the condition to be treated.
The person skilled in the art is familiar on the basis of his/her expert knowledge with excipients which are suitable for the desired pharmaceutical formulation. In addition to solvents, gel formers, suppository bases, tablet excipients and other active compound carriers, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers, agents for achieving a depot effect, buffer substances or colorants.
In one embodiment, the compounds of the formula I may also be combined with other pharmaceutical active compounds to achieve an advantageous therapeutic action. Thus, for example, in the treatment of cardiovascular conditions advantageous combinations with cardiovascular-active substances are possible. Suitable combination partners of this type which may be advantageous for cardiovascular conditions are, for example, other antiarrhythmics, i.e. class I, class II or class III antiarrhythmics, such as IKs or IKr channel blockers, e.g. dofetilide, or furthermore blood pressure-lowering substances such as ACE inhibitors (for example enalapril, captopril, ramipril), angiotensin antagonists, K+ channel activators, and also alpha- and beta-receptor blockers, but also sympathomimetic compounds and compounds having adrenergic activity, and also Na+/H+ exchange inhibitors, calcium channel antagonists, phosphodiesterase inhibitors and other substances having positive inotropic action, such as digitalis glycosides, or diuretics.
In one embodiment, for a form for oral administration, the active compounds are mixed with the additives suitable therefor, such as vehicles, stabilizers or inert diluents, and brought by means of the customary methods into the suitable administration forms, such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily solutions. Inert carriers which can be used are, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular cornstarch. In this case, preparation can be carried out, for example, either as dry or as moist granules. Possible oily vehicles or solvents are, for example, vegetable or animal oils, such as sunflower oil or cod liver oil. Possible solvents for aqueous or alcoholic solutions are, for example, water, ethanol or sugar solutions or mixtures thereof. Further excipients, also for other administration forms, are, for example, polyethylene glycols and polypropylene glycols.
For subcutaneous or intravenous administration, the active compounds, if desired with the substances customary therefor, such as solubilizers, emulsifiers or further excipients, are brought into solution, suspension or emulsion. The compounds of the formula I and their physiologically tolerable salts can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection or infusion preparations. Possible solvents are, for example, water, physiological saline solution or alcohols, e.g. ethanol, propanol, glycerol, in addition also sugar solutions such as glucose or mannitol solutions, or alternatively mixtures of the various solvents mentioned.
Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active compounds of the formula I or their physiologically tolerable salts in a pharmaceutically acceptable solvent, such as, ethanol or water, or a mixture of such solvents. If required, the formulation can also additionally contain other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers, and also a propellant. Such a preparation may contain the active compound, for example, in a concentration of about 0.1 to about 10, such as about 0.3 to about 3, percent by weight.
The dose of the active compound of the formula I to be administered or of the physiologically tolerable salts thereof depends on the individual case and is to be adapted to the conditions of the individual case as customary for an optimal action. Thus it depends, of course, on the frequency of administration and on the potency and duration of action of the compounds in each case employed for therapy or prophylaxis, but also on the nature and severity of the disease to be treated, and on the sex, age, weight and individual responsiveness of the human or animal to be treated and on whether therapy is carried out acutely or prophylactically. Customarily, the daily dose of a compound of the formula I when administered to a patient weighing approximately 75 kg is about 0.001 mg/kg of body weight to about 100 mg/kg of body weight, such as about 0.01 mg/kg of body weight to about 20 mg/kg of body weight. The dose, for example, can be administered in the form of an individual dose or in a number of doses, e.g. 2,3 or 4 individual doses. In particular when treating acute cases of cardiac arrhythmias, for example in an intensive care unit, parenteral administration by injection or infusion, e.g. by means of an intravenous continuous infusion, may be desired.